Ammonia → N-[1-Methyl-1-[6-(trifluoromethyl)-3-pyridinyl]ethyl]acetamide

HRID 1919801Notes

Reaction equation

HRID 1919801 reaction equation
[C:1](#[N:3])[CH3:2].[F:4][C:5]([F:17])([F:16])[C:6]1[N:11]=[CH:10][C:9]([C:12](O)([CH3:14])[CH3:13])=[CH:8][CH:7]=1.S(=O)(=O)(O)[OH:19].N>COC(C)(C)C.O>[CH3:13][C:12]([NH:3][C:1](=[O:19])[CH3:2])([C:9]1[CH:10]=[N:11][C:6]([C:5]([F:17])([F:16])[F:4])=[CH:7][CH:8]=1)[CH3:14]

Participants

7

Reactant 4

HCID 222AmmoniaHCID 1118Sulfuric AcidHCID 6342AcetonitrileHCID 534009962-[6-(Trifluoromethyl)pyridin-3-yl]propan-2-ol

Product 1

HCID 57951127N-[1-Methyl-1-[6-(trifluoromethyl)-3-pyridinyl]ethyl]acetamide

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 15413tert-Butyl methyl etherSolvent

Conditions

Temperature
2.5 °C

Procedure

Add acetonitrile (67.4 L; 53.0 kg) to a reaction vessel containing 2-(6-trifluoromethyl-pyridin-3-yl)-propan-2-ol (52 moles; 12.8 kg) and cool to 0-5° C. Add concentrated sulfuric acid (372 moles; 19.8 L; 36.5 kg) slowly, maintaining the internal reaction temperature between 0-15° C. Heat the solution to 25-30° C. for 24 hours, and observe the completion of the reaction by HPLC. Cool the mixture to 0° C. while stirring and add water (95.0 L; 95.0 kg). Add a solution of aqueous ammonia (57.5 kg) to adjust the solution pH to 8.0-9.0, and then add tert-butyl methyl ether (81.1 L; 60.0 kg). Separate the lower aqueous layer, concentrate the organic layer to approximately 3 volumes, and cool the contents of the reaction to −5-0° C. Filter the resultant solids and dry under vacuum until constant weight and collect (13.4 kg; 87.3%, based on HPLC) of the titled compound as a pale yellow solid in 81.8% purity. 1H NMR (DMSO-d6, 500 MHz): δ 8.68 (d, 1 H, J=2 Hz), 8.30 (s, 1 H), 7.92 (dd, 1 H, J=2.5, 8.5 Hz), 7.79 (d, 1 H, J=5.8 Hz), 1.82 (s, 3 H), 1.56 (s, 6 H).

Workup

  1. temperaturemaintaining the internal reaction temperature between 0-15° C
  2. temperatureHeat the solution to 25-30° C. for 24 hours
  3. customthe completion of the reaction by HPLC
  4. temperatureCool the mixture to 0° C.
  5. customSeparate the lower aqueous layer
  6. concentrationconcentrate the organic layer to approximately 3 volumes
  7. temperaturecool
  8. customthe contents of the reaction to −5-0° C
  9. filtrationFilter the resultant solids
  10. customdry under vacuum until constant weight
  11. customcollect (13.4 kg; 87.3%, based on HPLC) of the titled compound as a pale yellow solid in 81.8% purity

Sources & evidence

ORD record
ord-8e308fbb2c5c432abdc60839d5e29c72
Source dataset
uspto-grants-2012_05
Patent number
US08168659B2

Reaction notes

Loading…